It is an object of the invention to provide new compounds having valuable properties, particularly compounds which can be used for the preparation of medicaments.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
These objects are achieved by providing chroman derivatives of the formula I: ##STR2## wherein
R.sup.1 is A,
R.sup.2 and R.sup.8 are each H or A,
R.sup.1 and R.sup.2 together are also alkylene having 3-6 C atoms,
R.sup.3 is H, OH, OA or OAc,
R.sup.4 is H,
R.sup.3 and R.sup.4 together are also a bond,
R.sup.5 is a pyridyl-Z-, pyridazinyl-Z-, pyrimidinyl-Z-, pyrazinyl-Z-, oxo-dihydro-pyridyl-Z-, oxo-dihydropyridazinyl-Z-, oxo-dihydro-pyrimidinyl-Z-, oxo-dihydro-pyrazinyl-Z-, 1H-2-pyridon-1-yl,1H-6-pyridazinon-1-yl, 1H-2-pyrimidinon-1yl, 1H-6-pyrimidinon-1-yl, 1H-2-pyrazinon-1-yl or 1H-2-thiopyridon-1-yl radical which is unsubstituted or monosubstituted or disubstituted by A, F, Cl, Br, I, OH, AO, OAc, SH, NO.sub.2, NH.sub.2, AcNH, HOOC and/or AOOC, it being also possible for these radicals to be partially hydrogenated,
R.sup.6 and R.sup.7 are each H, A, HO, AO, CHO, ACO, ACS, HOOC, AOOC, AO--CS, ACOO, A--CS--O, hydroxyalkyl having 1-6 C atoms, mercaptoalkyl having 1-6 C atoms, NO.sub.2, NH.sub.2, NHA, NA.sub.2, CN, F, Cl, Br, I, CF.sub.3, ASO, ASO.sub.2, AO--SO, AO--SO.sub.2, AcNH, AO--CO--NH, H.sub.2 NSO, NANSO, A.sub.2 NSO, H.sub.2 NSO.sub.2, HANSO.sub.2, A.sub.2 NSO.sub.2, H.sub.2 NCO, HANCO, A.sub.2 NCO, H.sub.2 NCS, HANCS, A.sub.2 NCS, ASONH, ASO.sub.2 NH, AOSONH, AOSO.sub.2 NH, ACO-alkyl, nitroalkyl, cyanoalkyl, A--C(.dbd.NOH) or A--E(.dbd.NNH.sub.2),
Z is O, S or NH,
A is alkyl having 1-6 C atoms,
alkyl is alkylene having 1-6 C atoms and
Ac is alkanoyl having 1-8 C atoms or aroyl having 7-11 C atoms, and also to salts thereof.
In the foregoing, selection of variables defined together is made independently.
It has been found that the compounds of formula I and their physiologically acceptable salts possess valuable pharmacological properties and are well tolerated. Thus they exhibit an action on the cardiovascular system in which, as a rule, a selective attack on the coronary system can be observed at fairly low doses and a hypotensive effect can be observed at fairly high doses. Examples of effects on the coronary system are a decrease in resistance and increase in flow, while the effect on the heart rate remains small. The compounds also have a relaxing action on various smooth muscle organs (the gastro-intestinal tract, the-respiratory system and the uterus). The action of the compounds can be measured by means of methods which are known per se, such as are indicated, for example, EP-A1-76,075, EP-A1-173,848 or AU-A 45,547/85 (Derwent Farmdoc No. 86,081,769) and by K. S. Meesmann et al., Arzneimittelforschung 25 (11), 1975, 1770-1776. Examples of suitable experimental animals are mice, rats, guinea-pigs, dogs, cats, monkeys or pigs.
The compounds can therefore be used as active compounds for medicaments in human and veterinary medicine. They can also be used as intermediate products for the preparation of further active compounds for medicaments.
In the formulae indicated, A is an alkyl group which is preferably unbranched and has 1-6, preferably 1-4 and especially 1, 2 or 3, C atoms, specifically preferably methyl, and also preferably ethyl, propyl, isopropyl, butyl or isobutyl, and also preferably sec.-butyl, tert.-butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4-methylpentyl).
If R.sup.1 and R.sup.2 together are alkylene, the alkylene group is preferably unbranched and is specifically preferably --(CH.sub.2).sub.n -- wherein n is 3, 4, 5 or 6.
The group "alkyl" is preferably --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --.
Ac is preferably alkanoyl having 1-6, in particular 1, 2, 3 or 4, C atoms, specifically preferably formyl or acetyl, and also preferably propionyl, butyryl, isobutyryl, pentanoyl or hexanoyl, and also preferably benzoyl, o-, m- or p-toluyl, 1-naphthoyl or 2-naphthoyl.
R.sup.1 and R.sup.2 are preferably each alkyl, particularly each methyl or ethyl and preferably each methyl.
R.sup.3 and R.sup.4 are preferably, together, a bond. If R.sup.4 is H, R.sup.3 is preferably OH, O--CHO or O--COCH.sub.3.
R.sup.5 is preferably unsubstituted 1H-2-pyridon-1 -yl or 1H-2-pyrazinon-1-yl and also preferably unsubstituted 1H-6-pyridazinon-1-yl, 4,5-dihydro-1H-6-pyridazinon-1-yl, 1H-2-pyrimidinon-1-yl, 1H-6-pyrimidinon-1-yl or 1H-2-thiopyridon-1-yl. If R.sup.5 is a substituted pyridone or thiopyridone ring, this ring is preferably monosubstituted in the 3-, 4- or 5-position or is disubstituted in the 3-position and the 5-position. Substituents which are particularly preferred are NO.sub.2 and NH.sub.2, and also AOOC, OA, Cl, Br and NHCOCH.sub.3. Substituted radicals R.sup.5 which are particularly preferred are specifically 3-, 4-, 5- or 6-methoxy-, 3-, 4-, 5- or 6-acetoxy-, 3-, 5- or 6-chloro-, 3-nitro- or 5-nitro-, 3-amino- or 5-amino-, 3-carboxy- or 5-carboxy-, 3-methoxycarbonyl- or 5-methoxycarbonyl-, 3-ethoxycarbonyl- or 5-ethoxycarbonyl-, 3-acetamido- or 5-acetamido-, 3,5-dichloro-, 3,5-dibromo-, 3-chloro-5-nitro-, 3-nitro-5-chloro-, 3-bromo-5-nitro-, 3-nitro-5-bromo-, 3,5-dinitro-, 3-chloro-5-amino-, 3-amino-5-chloro-, bromo-5-amino-, 3-amino-5-bromo-, 3-chloro-5-acetamido-, 3-acetamido-5-chloro-, 3-bromo-5-acetamido- and 3-acetamido-5-bromo-1H-2-pyridon-1-yl or -1H-2-thiopyridon-1-yl,1H-3-, 1H-4- or 1H-5-ethoxycarbonyl-6-pyridazinon-1-yl.
R.sup.5 can also preferably be: 3,4-dihydro-1H-2-pyridon-1-yl, 2,3-dihydro-6H-2-pyridon-1-yl, 5,6-dihydro-1H-2-pyridon-1-yl, 2,3-dihydro-1H-6-pyridazinon-1-yl, 1,2-dihydro-5H-6-pyridazinon-1-yl, 3,4-dihydro-1H-2-pyrimidinon-1-yl, 1,6-dihydro-3H-2-pyrimidinon-1-yl, 5,6-dihydro-1H-2-pyrimidinon-1-yl, 2,3-dihydro-1H-6-pyrimidinon-1-yl, 1,2-dihydro-5H-6-pyrimidinon-1-yl, 4,5-dihydro-1H-6-pyrimidinon-1-yl, 3,4-dihydro-1H-2-pyrazinon-1-yl, 1,6-dihydro-3H-2-pyrazinon-1-yl, 5,6-dihydro-1N-2-pyrazinon-1-yl, 3,4-dihydro-1H-2-thiopyridon-1-yl, 2,3-dihydro-6H-2-thiopyridon-1-yl or 5,6-dihydro-1H-2-thiopyridon-1-yl.
Furthermore, R is preferably 6-hydroxy-3-pyridazinyl-Z(.dbd.1,6-dihydro-6-oxo-3-pyridazinyl-Z-) or 2-hydroxy-4-pyridyl-Z- (.dbd.1,2-dihydro-2-oxo-4-pyridyl-Z-), and in addition preferably unsubstituted 2-, 3- or 4-pyridyl-Z-, 2-, 4- or 5-pyrimidinyl-Z-, 3-, 4- or 5-pyridazinyl-Z or pyrazinyl-Z-, hydroxypyridyl-Z- such as 3-, 4-, 5- or 6-hydroxy-2-pyridyl-Z-, 2-, 4- or 5-hydroxy-3-pyridyl-Z-, 3-hydroxy-5-pyridyl-Z-, 2-hydroxy-5-pyridyl-Z-; hydroxypyridazinyl-Z- such as 4- or 5-hydroxy-3-pyridazinyl-Z-, 3-, 5- or 6-hydroxy-4-pyridazinyl-Z-; hydroxypyrimidinyl-Z- such as 4- or 5-hydroxy-2-pyrimidinyl-Z-, 2-, 5- or 6-hydroxy-4-pyrimidinyl-Z-, 2- or 4-hydroxy-5-pyrimidinyl-Z-; hydroxypyrazinyl-Z- such as 3-, 5- or 6-hydroxy-2-pyrazinyl-Z-; dihydroalkyloxopyridyl-Z-, such as 1,2-dihydro-l-methyl-2-oxo-3-, -4-, -5- or -6 -pyridyl-Z-, 1,2-dihydro-1-ethyl-2-oxo-3-, -4-, -5- or -6-pyridyl-Z-; dihydroalkyloxopyridazinyl-Z- such as 1,6-dihydro-l-methyl-6-oxo-3-, -4or -5-pyridazinyl-Z-, 1,6-dihydro-l-ethyl-6-oxo-3-, -4-, or -5-pyridazinyl-Z-; alkoxypyridyl-Z- such as 3-, 4-, 5- or 6-methoxy-2-pyridyl-Z-, 2-, 4- or 5-methoxy-3-pyridyl-Z-, 2- or 3-methoxy-4-pyridyl-Z-, 2-methoxy-5-pyridyl-Z-, 2- or 3-ethoxy-4-pyridyl-Z-; alkoxy-pyridazinyl -Z- such as 4-, 5- or 6-methoxy-3-pyridazinyl-Z-, 4-, 5- or 6-ethoxypyridazinyl-Z-, 3-, 5- or 6-methoxy-4-pyridazinyl-Z-, 3-, 5- or 6-ethoxy-4-pyridazinyl-Z-; alkoxypyrimidinyl-Z- such as 4- or 5-methoxy-2-pyrimidinyl-Z-, 2-, 5- or 6-methoxy-4-pyrimidinyl-Z-, 2- or 4-methoxy-5-pyrimidinyl-Z-: alkoxypyrazinyl-Z- such as 3-, 5- or 6-methoxy-2 -pyrazinyl-Z-; aminopyridyl-Z- such as 3-, 4-, 5- or 6-amino-2-p-pyridyl-Z-, 2-, 4- or 5-amino-3-pyridyl-Z-, 2- or 3-amino-4-pyridyl-Z-, 2-amino-5-pyridyl-Z-; aminopyridazinyl-Z- such as 4-, 5- or 6-amino- 3-pyridazinyl-Z-, 3-, 5- or 6-amino-4-pyridazinyl-Z-; aminopyrimidinyl-Z- such as 4- or 5-amino-2-pyrimidinyl-Z-; 2-, 5- or 6-amino-4-pyrimidinyl-Z-, 2- or 4-amino-5-pyrimidinyl-Z-; aminopyrazinyl-Z- such as 3-, 5- or 6-amino-2-pyrazinyl-Z-; mercaptopyridyl-Z- such as 3-, 4-, 5- or 6-mercapto-2-pyridyl-Z-, 2-, 4- or 5-mercapto-3-pyridyl-Z-, 2-(.dbd.1,2-dihydro-2-thioxo-4-pyridyl-Z-) or 3-mercapto-4-pyridyl-Z-, 2-mercapto-5-pyridyl-Z-; mercaptopyridazinyl-Z- such as 4-, 5- or 6-mercapto-3-pyridazinyl-Z- (.dbd.1,6-dihydro-6-thioxo-3-pyridazinyl-Z-), 3-, 5- or 6-mercapto-4-pyridazinyl-Z-; mercaptopyrimidinyl-Z- such as 4- or 5-mercapto-2-pyrimidinyl-Z-, 2-, 5- or 6-mercapto-4-pyrimidinyl-Z-, 2- or 4-mercapto-5-pyrimidinyl-Z-; mercaptopyrazinyl-Z- such as 3-, 5- or 6-mercapto-2-pyrazinyl-Z-.
Radicals of the type R.sup.3 which contain a hydroxyl or mercapto group adjacent to a ring N atom may also exist in the tautomeric lactam or thiolactam form, as indicated above in individual cases.
The radical -Z- is preferably --O--.
In R.sup.6 and R.sup.7 the symbols are preferably as follows:
A: methyl and also ethyl;
AO: methoxy and also ethoxy;
ACO: acetyl and also propionyl;
ACS: thioacetyl and also thiopropionyl;
AOOC: methoxycarbonyl and also ethoxycarbonyl;
AO-CS: methoxythiocarbonyl and also ethoxythiocarbonyl;
ACOO: acetoxy and also propionoxy;
A-CS-O: thio(no)acetoxy and also thio(no)propionoxy;
hydroxyalkyl: hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl;
mercaptoalkyl: mercaptomethyl, 1-mercaptoethyl or 2-mercaptoethyl;
NHA: methylamino and also ethylamino;
NA.sub.2 : dimethylamino and also diethylamino;
ASO: methylsulfinyl and also ethylsulfinyl;
ASO.sub.2 : methylsulfonyl and also ethylsulfonyl;
AO-SO: methoxysulfinyl and also ethoxysulfinyl;
AO-SO.sub.2 : methoxysulfonyl and also ethoxysulfonyl;
Ac-NN: acetamido and also formamido, propionamido benzamido;
AO-CO-NH: methoxycarbonylamino and also ethoxycarbonylamino;
HANSO: methylaminosulfinyl and also ethylaminosulfinyl;
A.sub.2 NSO: dimethylaminosulfinyl and also diethylaminosulfinyl;
HANSO.sub.2 :methyl aminosulfonyl and also ethylaminosulfonyl;
A.sub.2 NSO.sub.2 : dimethylaminosulfonyl and also diethylaminosulfonyl;
HANCO: N-methyl carbamoyl and also N-ethylcarbamoyl;
A.sub.2 NOC: N,N-dimethylcarbamoyl and also N,N-diethylcarbamoyl;
HANCS: N-methyl thiocarbamoyl and also N-ethylthiocarbamoyl;
A.sub.2 NCS: N,N-dimethylthiocarbamoyl and also N,N-diethylthiocarbamoyl;
ASONH: methylsulfinylamino and also methylsulfinylamino;
ASO.sub.2 NH: methylsulfonylamino and also ethylsulfonylamino;
AOSONH: methoxysulfinylamino and also ethoxysulfinylamino;
AOSO.sub.2 NH: methoxysulfonylamino and also ethoxysulfonylamino;
ACO-alkyl: 2-oxopropyl, 2-oxobutyl, 3-oxobutyl or 3-oxopentyl;
nitroalkyl: nitromethyl, 1-nitroethyl or 2-nitroethyl;
cyanoalkyl: cyanomethyl, 1-cyanoethyl or 2-cyanoethyl;
A-C(.dbd.NOH): 1-oximinoethyl and also 1-oximinopropyl;
A-C(.dbd.NNH.sub.2): 1-hydrazonoethyl and also 1-hydrazonopropyl.
The radicals R.sup.6 and R.sup.7 are preferably in the 6-position and 7-position of the chroman system. They can, however, also be in the 5- and 6-, 5- and 7-, 5- and 8-, 6- and 8-position and in the 7- and 8-position.
One of the radicals R.sup.6 and R.sup.7 is preferably H, while the other is different from H. This other radical is preferably in the 6-position, but can also be in the 5-, 7- or 8-position, and is preferably CN or NO.sub.2, and also preferably CHO, ACO (particularly acetyl), AOOC (particularly methoxycarbonyl or ethoxycarbonyl) or ACOO (particularly acetoxy), and also preferably F, Cl, Br, I, CF.sub.3, H.sub.2 NCO, H.sub.2 NCS or NH.sub.2.
The radical R.sup.8 is preferably H and furthermore preferably methyl or ethyl. Accordingly, the invention relates particularly to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings mentioned above. Some preferred groups of compounds can be expressed by means of the formulae Ia to Ii below, which correspond to the formula I and in which the radicals not indicated in detail have the meaning indicated in the formula I, but in which
in Ia: R.sup.1 and R.sup.2 are each A;
in Ib: R.sup.1 and R.sup.2 are each CH.sup.3 ;
in Ic: R.sup.1 and R.sup.2 together are alkylene having 3-6 C atoms;
in Id: R.sup.5 is 1H-2-pyridon-1-yl, 1H-2-pyrazinon-1-yl, 1H-6-pyridazinon-1-yl, 4,5-dihydro-1H-6-pyridazinon-1-yl, 1H-2-pyrimidinon-1-yl, 1H-6-pyrimidinon-1-yl, 1H-2-thiopyridon-1-yl, 3-, 4-, 5- or 6-methoxy-, 3-, 4-, 5- or 6-acetoxy-, 3-, 5- or 6-chloro-, 3-nitro- or 5-nitro-, 3-amino- or 5-amino-, 3-carboxy- or 5-carboxy-, 3-methoxycarbonyl- or 5-methoxycarbonyl-, 3-ethoxycarbonyl- or 5-ethoxycarbonyl-, 3-acetamido- or 5-acetamido-, 3,5-dichloro-, 3,5-dibromo-, 3-chloro-5-nitro-, 3-nitro-5-chloro-, 3-bromo-5-nitro-, 3-nitro-5-bromo-, 3,5 -dinitro-, 3-chloro-5-amino-, 3-amino-5-chloro-, 3-bromo-5-amino-, 3-amino-5-bromo-, 3-chloro-5-acetamido-, 3-acetamido-5-chloro-, 3-bromo- 5-acetamido- or 3-acetamido-5-bromo-1H-2-pyridon-1-yl or -1H-2-thiopyridon-1-yl, 1H-3-, 1H-4- or 1H-5-ethoxycarbonyl-6-pyridazinon-1-yl
in Ie: R.sup.5 is 1H-2-pyridon-1-yl or 1H-2-pyrazinon-1yl
in If: R.sup.5 is 1H-2-pyridon-1-yl;
in Ig: R.sup.1 and R.sup.2 are each CH.sub.3 and R.sup.5 is 1H-2-pyridon-1-yl, 1H-2-pyrazinon-1-yl, 1H-6-pyridazinon-1-yl, 4,5-dihydro-1H-6-pyridazinon-1-yl, 1H-2-pyrimidinon-1-yl, 1H-6-pyrimidinon-1-yl , 1H-2-thiopyridon-1-yl, 3-, 4-, 5- or 6-methoxy-, 3-, 4-, 5- or 6-acetoxy-, 3-, 5- or 6-chloro-, 3-nitro- or 5-nitro-, 3-amino- or 5-amino-, 3-carboxy- or 5-carboxy, 3-methoxycarbonyl- or 5-methoxycarbonyl-, 3-ethoxycarbonyl- or 5-ethoxycarbonyl-, 3-acetamido- or 5-acetamido-, 3,5-dichloro-, 3,5-dibromo-, 3-chloro-5-nitro-, 3-nitro-5-chloro-, 3-bromo-5-nitro-, 3-nitro-5-bromo-, 3,5-dinitro-, 3-chloro-5-amino-, 3-amino-5-chloro-, 3-bromo-5-amino-, 3-amino-5-bromo-, 3-chloro-5-acetamido-, 3-acetamido-5-chloro-, 3-bromo-5-acetamido- or 3-acetamido-5-bromo-1H-2-pyridon-1-yl or -1H-2-thiopyridon-1H-6-pyridazinon-1-yl, 4,5-dihydro-1H-6
1-yl, 1H-3-, 1H-4- or 1H-5-ethoxycarbonyl-6-pyridazinon-1-yl
in Ih: R.sup.1 and R.sup.2 are each CH.sub.3 and R.sup.5 is 1H-2-pyridon-1-yl or 1H-2-pyrazinon-1-yl; and
in Ii: R.sup.1 and R.sup.2 are each CH.sub.3 and R.sup.5 is 1H-2-pyridon-1-yl.
Compounds of the formulae I' and Ia' to Ii' which correspond to the formulae I and Ia to Ii, but in which in each case R.sup.3 additionally is OH, OCHO or OCOCH.sub.3 and R.sup.4 is additionally H are also preferred.
Compounds of the formulae I" and Ia" to Ii" which correspond to the formulae I and Ia to Ii, but in which in each case R.sup.3 and R.sup.4 together are additionally a bond are also preferred.
Compounds of the formulae I, I', I", Ia to Ii, Ia' to Ii' and Ia" to Ii" in which, in each case, additionally
(a) R.sup.6 is other than H and R.sup.7 is H;
(b) R.sup.6 other than H and is in the 6-position and R.sup.7 is H;
(c) R.sup.6 is NO.sub.2, CN, CHO, ACO, HOOC, AOOC, ACOO, F, Cl, Br, I, CF.sub.3, H.sub.2 NCO, H.sub.2 NCS or NH.sub.2 and R.sup.7 is H;
(d) R.sup.6 is NO.sub.2, CN, CHO, ACO, HOOC, AOOC, ACOO, F, Cl, Br, I, CF.sub.3, H.sub.2 NCO, H.sub.2 NCS or NH.sub.2 and is in the 6-position and R.sup.7 is H;
(e) R.sup.6 is NO.sub.2, CN, CHO, CH.sub.3 CO, CH.sub.3 OOC, , C.sub.2 H.sub.5 OOC or CH.sub.3 COO and R.sup.7
(f) R.sup.6 is NO.sub.2, CN, CHO, CH.sub.3 CO, CH.sub.3 OOC, C.sub.2 H.sub.5 OOC or CH.sub.3 COO and is in the 6-position and R.sup.7 is H;
(g) R.sup.6 is NO.sub.2 or CN and R.sup.7 is H;
(h) R.sup.6 is NO.sub.2 or CN and is in the 6-position and R.sup.7 is H;
(i) R.sup.6 is CN and R.sup.7 is H;
(j) R.sup.6 is CN and is in the 6-position and R.sup.7 is H, are also preferred.
Among the compounds of all preceding formulae, those are preferred wherein (a) R.sup.8 is H, (b) R.sup.8 is CH.sub.3.
Incidentally, in the preceding and following text, the radicals R.sup.1 to R.sup.8, A, "alkyl" and Ac have the meanings indicated in formula I unless anything to the contrary is expressly indicated.
The invention also relates to a process for the preparation of the compounds of the formula I and their salts, which is characterized in that a 3,4-epoxychroman of the formula II ##STR3## wherein --X--Y-- is ##STR4## or --CHE--CR.sup.3 R.sup.8 --, E is Cl, Br, I or a reactively esterified OH group, and R.sup.1, R.sup.2, R.sup.3, R.sup.6, R.sup.7 and R.sup.8 have the meaning indicated in formula I, is reacted with a compound of the formula III EQU R.sup.5 --H III
wherein R.sup.5 has the meaning indicated in formula I, or with one of its reactive derivatives,
and/or a compound of the formula I, wherein R.sup.3 is OH and R.sup.4 is H is dehydrated, and/or in a compound of the formula I one or more of the radicals R.sup.3, R.sup.5, R.sup.6 and/or R.sup.7 are converted into to other radicals R.sup.3, R.sup.5, R.sup.6 and/or R.sup.7 and/or a basic compound of the formula I is converted into one of its acid addition salts by treatment with an acid.
The compounds of the formula I are, incidentally, prepared by methods which are known per se, such as are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie ("Methods of Organic Chemistry"), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York; and in the patent applications indicated above) and specifically under reaction conditions which are known and suitable for the reactions mentioned. In this regard it is also possible to make use of variants which are known per se but are not mentioned here in detail.
If desired, the starting materials can also be formed in situ in such a way that they are not isolated from the reaction mixture, but are immediately reacted further to give the compounds of the formula I.
The compounds of the formula I are preferably prepared by reacting compounds of the formula II with compounds of the formula III, preferably in the presence of an inert solvent, at temperatures between about 0.degree. and 150.degree..
Starting materials of the formula II with ##STR5## (3,4-epoxychromans) are preferred.
The starting materials II and III are usually known. If they are not known, they can be prepared by methods which are known per se. Thus, the starting materials of the formula II ##STR6## are obtainable by reacting 2-hydroxyacetophenones of the formula 2-HO-R.sup.6 R.sup.7 C.sub.6 H.sub.2 -COCH.sub.3 with ketones of the formula R.sup.1 -CO-R.sup.2 to give corresponding 4-chromanones of the formula IVa ##STR7## if desired condensing with aldehydes of the formula R.sup.9 -CHO (R.sup.9 =alkyl having 1-5 C atoms) to give 3-alkylidene-4-chromanones of the formula IVb, reducing, for example with NaBH.sub.4, to give chromanols of the formula IVc, dehydrating, for example with p-toluenesulfonic acid, to give chromenes of the formula IVd and oxidizing, for example with 3-chloroperbenzoic acid. The last-mentioned oxidation can also be carried out in a number of steps. Thus, for example, the bromohydrins of the formula IVe can initially be prepared using N-bromosuccinimide in aqueous solution and HBr can subsequently be eliminated from these using a base, for example sodium hydroxide solution.
The chromenes of the formula IVd can also be obtained by condensation of salicylaldehydes of the formula 2-HO-R.sup.6 R.sup.7 C.sub.6 H.sub.2 -CHO with ketones of the formula R.sup.1 -CO-CH.sub.2 -R.sup.8 to give hydroxyketones of the formula 2-HO-R.sup.6 R.sup.7 C.sub.6 H.sub.2 -CH.vertline.CR.sup.8 -CO-R.sup.1, reaction with organolithium compounds of the formula R.sup.2 -Li and subsequent hydrolysis to give diols of the formula 2-HO-R.sup.6 R.sup.7 C.sub.6 H.sub.2 -CH.dbd.CR.sup.8 -CR.sup.1 R.sup.2 -OH, and cyclization with elimination of water.
In compounds of the formula II (--X--Y--.dbd.--CHE--CR.sup.3 R.sup.8 -), possible "reactively esterified OH groups" are in particular esters with alkylsulfonic acids (in which the alkyl group contains 1-6 C atoms ) or with arylsulfonic acids (in which the aryl group contains 6-10 C atoms). These compounds are obtainable from the 4-chromanols of the formula IVc by reacting with an inorganic acid halide such as PCl.sub.3, PBr.sub.3, SOCl.sub.2 or SOBr.sub.2 or with a sulfonyl chloride such as methanesulfonyl or p-toluenesulfonyl chloride.
Starting materials of the formula II (R.sup.8 H) can be obtained by reacting propargyl chlorides of the formula HC.dbd.C--CR.sup.1 R.sup.2 --Cl with phenols of the formula R.sup.6 R.sup.7 C.sub.6 H.sub.3 OH to give phenol ethers of the formula .sup.6 R.sup.7 C.sub.6 H.sub.3 O--CR.sup.1 R.sup.2 --C.dbd.CH, cyclizing the products to give chromenes corresponding to formula IVd (R.sup.8 .dbd.H), adding on a molecule of HOBr to give the bromohydrin of formula IVe ( R.sup.8 .dbd.H) and dehydrobrominating the product (for method cf., for example, EP-A1-76,075).
Suitable reactive derivatives of III are the corresponding salts, for example the Na or K salts, which can also be formed in situ.
It is preferable to carry out the reaction of II with III in the presence of a base. Examples of suitable bases are alkali metal hydroxides, hydrides or amides or alkaline earth metal hydroxides, hydrides or amides, such as NaOH, KOH, Ca(OH).sub.2, NaH, KH, CaH.sub.2, NaNH.sub.2 or KNH.sub.2, and also organic bases, such as triethylamine or pyridine, which can also be used in excess and can then at the same time act as the solvent.
Suitable inert solvents are, in particular, alcohols,.such as methanol, ethanol, isopropanol, n-butanol or tert.-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methylglycol or ethylglycol) or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; nitriles, such as acetonitrile; nitro compounds, such as nitromethane or nitrobenzene;. esters, such as ethyl acetate; amides, such as dimethylformamide (DMF), dimethylacetamide or phosphoric acid hexamethyltriamide; sulfoxides, such as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons, such as methylene dichloride, chloroform, trichloroethylene, 1,2-dichloroethane or carbon tetrachloride; or hydrocarbons, such as benzene, toluene or xylene. Mixtures of these solvents with one another are also suitable.
The epoxide II can also be prepared in situ, for example by the action of a base on the corresponding bromohydrin IVe.
Different products of formula I can be formed by the reaction of II with III, dependent in particular from the structure of the starting materials and from the reaction conditions.
For instance, the formation of compounds of formula I containing an oxygen bridge (R.sup.5 =unsubstituted or substituted pyridyl-oxy, pyridazinyl-oxy, pyrimidinyl-oxy, pyrazinyl-oxy, oxo-dihydro-pyridyl-oxy, oxo-dihydropyridazinyl-oxy, oxo-dihydro-pyrimidinyl-oxy or oxodihydro-pyrazinyl-oxy) is favored if the compound III contains at least one OH group as a substituent in addition to the lactame or lactime group and/or if the reaction is carried out under relatively mild conditions, e.g., in the presence of a weak base such as pyridine in an alcohol. For instance, from 2,2,3-trimethyl- 3,4-epoxy-6-cyano-chromane ("IIb") and 1H-2-pyridone with NaH in DMSO there are formed predominantly 2,2,3 -trimethyl-4-(1H-2-pyridon-1-yl )-6-cyano-2H-chromene ("C") and 2,2,3-trimethyl-4-(1H-2-pyridon-1-yl )-6-cyano-chroman-3-ol ("D") whereas with pyridine in ethanol there are formed about equal parts of "D" and 2,2,3-trimethyl-4-(2-pyridyl-oxy)-6-cyano-chroman-3-ol. From 2,4-dihydroxypyridine (=4-hydroxy-1H-2-pyridone) and IIb in pyridine/ethanol there are formed 2,2,3 -trimethyl-4-(2-hydroxy-4-pyridyl-oxy )-6-cyano-chroman-3-ol and 2,2,3 -trimethyl -4-(4-hydroxy-1H-2 -pyridon-1-yl )-6-cyano-chroman-3-ol in a weight ratio of about 9:1.
In each single case optimal reaction conditions can be worked out easily. The reaction products, can be separated and isolated without difficulties, e.g., by crystallization and/or chromatography.
A compound of the formula I wherein R.sup.3 is ON and R.sup.4 is H can be converted by treatment with a dehydrating agent into a compound of the formula I wherein R.sup.3 and R.sup.4 together are a bond. This is effected, for example, by the action of one of the bases indicated, for example Nail, in one of the solvents indicated, for example DRSO, at temperatures between 0.degree. and 150.degree..
It is also possible to convert one or more of the radicals R.sup.3, R.sup.5, R.sup.6 and/or R.sup.7 in a compound of the formula I into other radicals R.sup.3, R.sup.5, R.sup.6 and/or R.sup.7.
For example, it is possible to replace an H atom by a halogen atom by halogenation or to replace an H atom by a nitro group by nitration and/or to reduce a nitro group to an amino group and/or to alkylate or acylate an amino or hydroxyl group and/or to convert a cyano group into a carboxyl group (for example by means of HCl in water/methanol at 20.degree.-100.degree. ) or into a formyl group (for example by means of Raney nickel in water/acetic acid/pyridine in the presence of sodium phosphate) or into a carbamoyl group (for example by means of KOH in tert.-butanol) or into a thiocarbamoyl group (for example by means of H.sub.2 S in pyridine/triethylamine) and/or to convert a -CO-NH-group (for example by means of P.sub.2 S.sub.5 or by means of Lawesson reagent in toluene) into a -CS-NH- or -C(SH).dbd.N- group.
A nitration reaction is carried out under customary conditions, for example using a mixture of concentrated HNO.sub.3 and concentrated H.sub.2 SO.sub.4 at temperatures between 0.degree. and 30.degree.. If at least one of the substituents R.sup.6 and R.sup.7 is an electronegative group, such as CN or NO.sub.2, the nitration takes place predominantly on the R.sup.5 radical; otherwise mixtures in which the nitro groups can be on the R.sup.5 radical or in the chroman ring are usually obtained.
Analogous considerations apply to halogenation, which can be carried out, for example, using elementary chlorine or bromine in one of the customary inert solvents at temperatures between about 0.degree. and 30.degree..
A primary or secondary amino group and/or an OH group can be converted by treatment with alkylating agents into the corresponding secondary or tertiary amino group and/or alkoxy group. Examples of suitable alkylating agents are compounds of the formulae A-Cl, A-Br or A-I or corresponding sulfuric acid esters or sulfonic acid esters, such as methyl chloride, bromide or iodide, dimethyl sulfate or methyl p-toluenesulfonate, It is also possible, for example, to introduce one or two methyl groups by means of formaldehyde in the presence of formic acid, The alkylation is preferably carried out in the presence or absence of one of the inert solvents mentioned, for example DMF, at temperatures between about 0.degree. and about 120.degree., and a catalyst can also be present, preferably a base, such as potassium tert.-butylate or NaH.
Suitable acylating agents for the acylation of amino or hydroxyl groups are preferably the halides (for example chlorides or bromides) or anhydrides of carboxylic acids of the formula Ac-OH, for example acetic anhydride, propionyl chloride, isobutyryl bromide, formic/acetic anhydride or benzoyl chloride. It is possible to add a base, such as pyridine or triethylamine, during the acylation. It is preferable to carry out the acylation in the presence or absence of an inert solvent, for example a hydrocarbon, such as toluene, a nitrile, such as acetonitrile, an amide, such as DMF, or an excess of a tertiary base, such as pyridine or triethylamine, at temperatures between about 0.degree. and about 160.degree. preferably between 20.degree. and 120.degree.. Formylation can also be carried out by means of formic acid in the presence of pyridine.
A base of the formula I can be converted into the appropriate acid addition salt by means of an acid. Acids which afford physiologically acceptable salts are particularly suitable for this reaction. Thus it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrogen halide acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, and sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic, monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimetic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic or 3-phenylpropionic, acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene monosulfonic and naphthalene disulfonic acids, and laurylsulfuric acid, Salts with physiologically unacceptable acids, for example picrates, can be used to purify the compounds of the formula I.
The compounds of the formula I can contain one or more chiral centers. When they are prepared, therefore, they can be obtained in the form of racemates or, if optically active starting materials are used, also in an optically active form. If the compounds have two or more chiral centers, they can be produced, in the synthesis, as mixtures of racemates, from which the individual racemates can be isolated in a pure form, for example by recrystallization from inert solvents. Thus, for example, compounds of the formula I wherein R.sup.1 is R.sup.2, R.sup.3 is OH and R.sup.4 is H have two chiral centers; however, when they are prepared by reacting II with III the product formed is very predominantly only one racemate having the substituents R.sup.3 .dbd.OH and R.sup.5 in the trans-position. The resulting racemates can, if desired, be separated into their enantiomers by mechanical or chemical means, in accordance with methods known per se. Thus diastereomers can be formed from the racemate by reacting it with an optically active separating agent. Examples of suitable separating agents for basic compounds of the formula I are optically active acids, such as the D-forms and l-forms of tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, camphorsulfonic acids, mandelic acid, .malic acid or lactic acid. Carbinols (I, R.sup.3 .dbd.ON) can also be esterified by means of chiral acylating reagents, for example D-.alpha.-methylbenzyl isocyanate or l-.alpha.-methylbenzyl isocyanate, and can then be separated (cf. EP-A1-120,428). The different forms of the diastereomers can be separated in a manner known per se, for example by fractional crystallization, and the enantiomers of the formula I can be liberated from the diastereomers in a manner known per se. It is also possible to carry out separation of enantiomers by chromatography over optically active supporting materials.
Optically active compounds of formula I can, of course, be obtained from optically active starting materials, f.e. from the enantiomeric forms of the epoxides of formula II.
The compounds of the formula I and their physiologically acceptable salts can be used for the preparation of pharmaceutical formulations, particularly by a non-chemical route. In this regard they can be brought into a suitable dosage form together with at least one solid, liquid and/or semi-liquid excipient or auxiliary and, if appropriate, in combination with one or more further active compounds.
The invention also relates to agents, in particular pharmaceutical formulations, containing at least one compound of the formula I and/or one of its physiologically acceptable salts.
These formulations can be-used as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral) or parenteral administration or topical application and which do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose or starch. magnesium stearate, talc, lanolin or petroleum jelly. Tablets, coated tablets, capsules, syrups, elixirs or drops are especially used for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants are used for parenteral administration, while ointments, creams pastes, lotions, gels, sprays, foams, aerosols, solutions (for example solutions in alcohols such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propanediol or their mixtures with each other and/or with water) or powders are used for topical application. The new compounds can also be lyophilized,and the resulting lyophilizates can be used, for example, for the preparation of injection preparations. Liposomal preparations are in particular also suitable for topical application. The formulations described can be sterilized and/or can contain auxiliaries, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and flavorings and/or aroma substances. They can, if desired, also contain one or more further active compounds, for example one or more further active compounds, for example one or more vitamins.
The compounds of the formula I and their physiologically acceptable salts can be administered to humans or animals, in particular mammals, such as monkeys, dogs, cats, rats or mice, and can be used in the therapeutic treatment of the human or animal body and in combating diseases, particularly in the therapy and/or prophytaxis of disorders of the cardiovascular system, in particular decompensated cardiac insufficiency, angina pectoris, arrhythmia, peripheral or cerebral vascular diseases and also states of diseases which are associated with high blood pressure. They are also usable for combating disorders which are connected with changes in the non-vascular musculature, for example urinary incontinence. In addition, they are useful as bronchodilators, and thus for treatment of bronchial asthma, typically in the same dosage ranges as discussed below.
In this regard, the substances according to the invention are generally administered analogously to known anti-anginal agents or hypotensive agents, for example nicorandil or BRl-34915 [2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-6-cyanochroman-3-ol; cf. EP-A1-173,848], preferably in dosages between about 0.01 and 5 mg, especially between 0.02 and 0.5 mg, per dosage unit. The daily dosage is preferably between about 0.0001 and 0.1, in particular between 0.0003 and 0.01 mg/kg of body weight.
A preferred daily dosage range for the treatment of angina pectoris is 0.003 to 0.03 mg/kg of body weight.
The particular dose for each specific patient depends, however, on a very wide variety of factors, for example on the effectiveness of the particular compound employed, on the age, body weight, general state health, sex, on the diet, on the time and method of administration, on the rate of excretion, the combination of medicaments and the severity of the particular disease against which the therapy is used. Oral administration is preferred.
Preferred agents of this invention are "A" of Example 1 below and "(-)-B" of Example 25 below, e.g., for treating angina pectoris and/or for use as a coronary vasodilator.
The compounds of the formula I and their salts are also suitable, particularly in the case of topical use, for the treatment of alopecia, including androgenic alopecia and Alopecia areata. The pharmaceutical formulations used especially for this purpose are those which are suitable for topical treatment of the scalp and which are mentioned above. They contain about 0.005 to 10, preferably 0.5 to 3, % by weight of at least one compound of the formula I and/or at least one of its salts. In other respects these compounds can be used against alopecia analogously to the instructions in WO 88/00822.
The term "partially hydrogenated" in the definition of R.sup.5 above means that, in the radicals in question, instead of one C.dbd.C or one C.dbd.N double bond there may be a saturated CH--CH or CH--NH bond; with other words, this term means to include the dihydro derivatives of the cited radicals.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description; utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.